Another week, another COVID-19 study...

On August 12th, the Metcovid study was e-published ahead of print in Clinical Infectious Diseases.  This was another study looking at steroids in COVID-19 pneumonia, this time performed in Brazil.  Metcovid was a parallel, double-blind, randomized, placebo-controlled phase IIb clinical trial which enrolled 416 patients at a single academic center for the evaluation of methylprednisolone (MP; 0.5 mg/kg BID x 5 days) vs placebo.  As with all COVID studies, Metcovid has some significant limitations, and some equivocal findings.  However, Metcovid was largely in line with RECOVERY and other trials looking at steroids in COVID-19, which lends it some face validity.  Metcovid found no significant difference in the primary outcome (mortality at day 28), but did find a difference in mortality in patients over 60 years old (a post-hoc analysis).  Metcovid was probably underpowered (sample size was based on a 50% reduction in mortality), and did have a very small trend towards reduced mortality in the MP group (37.1% vs 38.2%, p=0.629).

Bottom Line: 

• Steroids (methylprednisolone 0.5 mg/kg BID x 5 days in this case) may have some mild benefit in severe cases of COVID-19 pneumonia, especially in patients who are elderly or have more aggressive inflammatory responses (as measured by CRP here).  
• Steroids in COVID-19 may be associated with some theoretical downsides like reduced viral clearance, but are relatively safe.  Main side effect is the well known hyperglycemia induced by corticosteroids.
• When using steroids in COVID pneumonia, both to stick with the evidence and for theoretical pharmacologic reasons, it may make sense to use dexamethasone or methylprednisolone, as these medications have a higher glucocorticoid:mineralocorticoid activity ratio.  It is hypothesized that using high mineralocorticoid steroids (like cortisone or hydrocortisone) may lead to increased water retention, which could be deterimental in ARDS.  This is purely theoretical.
• There was a signal towards harm in younger and less sick patients in this study, and it probably remains prudent to reserve steroids for older, sicker COVID-19 pneumonia patients, similar to the RECOVERY trial.

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What physical exam findings are associated with nitrous oxide abuse?

Nitrous oxide (NO) inhalation abuse, also called “whip-its” or “whippets”, inactivates vitamin B12 and create a vitamin B12 deficiency state. Chronic abuse of nitrous oxide can result in neurologic deficits/findings affecting the posterior/dorsal column of the spinal cord. 

Physical exam findings: 

1. Truncal ataxia
2. Decreased vibratory sensation and proprioception in lower extremities
3. Impaired coordination and rapid alternative movements
4. Lhermitte’s sign: paresthesia of the upper and lower extremities associated with flexion of the head/neck.
5. Rossolimo’s sign: exaggerated flexion of the toes when the tips of the toes are percussed

• Spontaneous cerebrospinal fluid (CSF) rhinorrhea is rare and usually related to a combination of thinning of the bone and dura and fluctuating intracranial pressure.
• CSF rhinorrhea can be associated with idiopathic intracranial hypertension, skull base tumors, neurosurgical and otolaryngology procedures, and trauma.
• Trauma with fracture of the anterior skull base is the most common cause of CSF rhinorrhea.
• CT and MRI can identify bony defects, whereas cisternography can diagnose occult leaks.
• Fluid containing CSF is classically described to make a “halo” or “double-ring” pattern on gauze or linen.

• However, this sign is not specific to CSF, as mixtures of blood with saline, tears, or rhinorrhea can also produce halos.
• Beta-2 transferrin is a protein found almost exclusively in CSF* thus can be used to diagnose CSF rhinorrhea.

Bottom Line: Beta-2 transferrin is more accurate than the halo sign to identify CSF containing fluid.

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While chest X ray (CXR) is routinely obtained in the setting of traumatic injury, ultrasound (US) is a fast and reliable way to evaluate for life-threatening traumatic injuries requiring emergent intervention, and is supported by the Eastern Association for the Surgery of Trauma (EAST) guidelines. A recent Cochrane Review compared the test characteristics of chest US vs CXR for detection of traumatic pneumothorax when using Chest CT or thoracostomy as the gold standard.

• Primary end point: sensitivity and specificity for pneumothorax
• US performed by nonradiologists.
• 9 studies, 1271 patients, 410 of which had a pneumothorax
• Summary sensitivity: US 0.91 (95% CI 0.85-0.94), ranging from  0.82-0.98 in the included studies, vs. CXR 0.47 (95% CI 0.31- 0.63) ranging from 0.09 to 0.75
• Summary specificity: US 0.99 (95% CI 0.97-1.00, ranging from  0.96-1.00 vs. CXR 1.00 (95% CI 0.97- 1.00), ranging from 0.98 to 1.00

There possible weaknesses of this study, including blinding in the original studies, and several studies may or may not have been at risk for bias as their risk of bias was ‘unclear’.  However, the results were consistent across the studies analyzed and remained similar after sensitivity analysis.

Several anatomical as well as patient care issues may confound US findings for pneumothorax such as the presence of bleb, prior thoracic surgery or pathology, as well as main stem intubation.

Bottom line:  While the presence of pneumothorax is on either CXR or US is highly likely to represent the a true pneumothorax, ultrasound is a far superior screen for the detection of pneumothorax in the trauma patient.

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Pronator Teres Syndrome

A compressive neuropathy of the median nerve in the region of the elbow

The median nerve passes through the cubital fossa and passes between the superficial and deep heads of the pronator teres muscle.

Rare compared to other compressive neuropathies such as carpal tunnel syndrome.

More common in women and in fifth decade of life

May be seen with weight lifters, arm wrestlers, rowers, tennis, archery, professional cyclists, dentists, fiddlers, pianists, harpists

Also associated with well-developed forearm muscles  

History:

Forearm pain – unlike carpal tunnel

Paresthesias in median distribution

No night symptoms – unlike carpal tunnel

Physical exam:

Sensory loss in medial nerve distribution.

Involves the thenar eminence!

Unlike carpal tunnel syndrome which doesn’t involve sensory loss in thenar eminence.

Pain may be made worse with resisted forearm pronation

Compression/Tinel’s sign over pronator mass reproduces symptoms

Treatment:

Splinting which limits pronation and NSAIDs

Steroid injection

Surgical nerve decompression is non operative treatment fails after greater than 6 months (rare)

Prior to this study, a Cochrane review and meta-analysis of TXA for upper GI bleeds with 7 trials (1654 patients), showed a large reduction in mortality with TXA (RR 0.61, 95% CI 0.42-0.98, p=0.01)

Design:

-Randomized, international, multicentre, placebo-controlled trial at 164 hospitals in 15 countries Juy 2013-2019

->16/18 years old with upper or lower GI bleeding

-1 g TXA IV over 10 minutes followed by maintenance dose 3 g TXA over 24 hours 

Results:

-Main outcome death due to bleeding within 5 days 

-4% (222/5994) died in TXA group vs 4% (226/5981) placebo risk ratio RR 0.99, 95% CI 0.82-1.18 

-Arterial thromboembolic events MI/CVA similar in both groups (0.7% vs 0.8%)

-Venous thromboembolic events PE/DVT higher in TXA group (0.8% vs 0.4%)

Pitfalls:

-Initially calculated all cause mortality until realization that over half deaths were due to non-bleeding causes, changed to death related to bleeding, allowing study appropriate power to detect difference 

-Majority of patients had UGIB/variceal bleeding due to liver disease, over 75% deaths in those with liver disease 

-Only 16% patients randomized in <3 hours, most >8 hours (CRASH-2 trial found benefit TXA in trauma patients only <3 hrs to administration) 

Takeaway:

-TXA should not be used in the management of GI bleeds

-Increased venous thromboembolic events associated with TXA administration for GI bleeds

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The liver performs an essential role in the metabolism and clearance of many drugs. Liver damage due to cirrhosis can decrease first-pass metabolism of oral medications and increase free-drug concentrations of protein-bound medications due to decreased albumin production. In the absence of cirrhosis, patients with chronic hepatitis or hepatic cancer may only have a small decrease in drug clearance. Hepatic dose adjustments are not as prevalent or readily available as renal dose adjustments, which can create difficulty in finding the balance between pain relief and adverse effects.

The most common medications used for pain control in the emergency department are acetaminophen, NSAIDs, and opioids.

Acetaminophen

It is sometimes misconceived that acetaminophen should never be used in patients with cirrhosis due to the common knowledge that acetaminophen overdoses can cause hepatotoxicity. Alcoholics may have an increased risk of hepatotoxicity due to induction of CYP2E1 and decreased glutathione stores. However, acetaminophen is safe in patients with cirrhosis when used at appropriate doses. Limit the total daily dose of acetaminophen to 2 g daily in patients with cirrhosis and avoid acetaminophen in patients that are actively drinking.  Also, educate patients that over-the-counter (OTC) and prescription medications may contain acetaminophen.

NSAIDs

In patients with cirrhosis, NSAIDs have increased bioavailability due to decreased CYP metabolism and decreased protein binding. In addition, prostaglandin inhibition can precipitate renal failure and sodium retention, worsening ascites and increasing the risk of hepatorenal syndrome, and increase the risk of gastrointestinal bleeding. Thrombocytopenia from NSAID use can further increase the risk of bleeding. Thus, avoid NSAID use in patients with cirrhosis. Topical NSAIDs can be considered.

Opioids

Opioid metabolism is altered in patients with cirrhosis and can contribute to complications with cirrhosis, such as precipitating encephalopathy. Generally, the bioavailability is increased and half-life is extended; thus, lower doses of immediate-release (IR) formulations at extended dosing intervals should be utilized. Common opioids for acute pain control in the emergency department are fentanyl, hydrocodone/oxycodone, hydromorphone, and morphine.

• Fentanyl: Largely unaffected by cirrhosis. High potency so utilize only in appropriate clinical situations.
• Hydrocodone/Oxycodone: Metabolized by CYP to active metabolites (hydromorphone/oxymorphone). Due to decreased CYP metabolism, analgesia may be less potent and clearance decreased. Also, be aware that some formulations are combined with acetaminophen.
• Hydromorphone: Metabolized by glucuronidation to inactive metabolite. Metabolism and clearance less affected by cirrhosis.
• Morphine: Increased bioavailability and concentration due to decreased first-pass metabolism. Decreased clearance and longer half-life. Avoid use in renal impairment and hepatorenal syndrome due to risk of neurotoxic metabolite accumulation.
• Tramadol, codeine, meperidine, methadone, and buprenorphine not recommended for acute pain control in the emergency department.

Take Home Points

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There is no well validated clinical decision rule similar to NEXUS or the Canadian Cervical Spine rule in children for clearing the cervical spine.  Clinical clearance versus imaging first is a complicated decision.  Certain risk factors may predispose children to injury and should be taken into account when deciding about clinical clearance versus imaging (XR).

High Risk Criteria for Cervical Spine Injury in Pediatrics

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Tianeptine is an antidepressant with mu-opioid receptor agonism. It is available in several European countries for therapeutic use, but not available in the US.

There has been an increase in tianeptine exposure in the US since August 2019. Recently a retrospective observation study was done to characterize the clinical features associated with tianeptine exposure. 

Result

• 48 cases of tianeptine exposure were identified from January 1, 2015 to March 15, 2020 from a single poison center
• 37 cases (77%) occurred from May 2019 to March 2020.

Conclusion

• Tianeptine exposure is increasing in the US .
• Intoxication frequently results in lethargy and/or agitation.

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Design
-Two-center prospective observational study with 157 patients admitted to the ICU for pneumonia and being treated with HFNC
-ROX (Respiratory rate-OXygenation) index = ratio of SpO2/FIO2 to RR

Results:
-ROX index ≥4.88 at 12 hours after HFNC onset with a sensitivity of 70.1%, a specificity of 72.4%, PPV of 89.4%, NPV of 42%, LR+ of 2.54, and LR- of 0.41 in predicting treatment failure

Validation study: Roca, 2019
-results similar, but ROX index ≥4.88 at 12 hour with LR+ of only 1.82
-also found that a ROX index of <3.85 at 12 hours had a sensitivity of 23.5%, specificity of 98.4%, PPV of 88.9, NPV 69.9, LR+ of 14.47, and LR- 0.78

Pitfalls:
-decision to intubate was not made based on ROX index
-criteria for intubation was also part of the ROX index
-NIV was not part of their treatment algorithm
-created and validated prior to current COVID-19 pandemic

Takeaways:
- The ROX index can be a tool to help predict whether a patient with pneumonia on HFNC may need mechanical ventilation or higher level of care
- May be most helpful with patients with pneumonia on HFNC boarding in the ED
- At 12 hours of HFNC, ROX index of >4.88 suggests patient likely to succeed with HFNC vs. <3.85 which suggests likely need for mechanical ventilation

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The RECOVERY (Randomized Evaluation of COVid-19 thERapY) investigators recently published a non-peer reviewed article on their findings utilizing dexamethasone to treat patients with COVID-19. 

Rx: Dexamethasone 6mg daily* x 10 days (PO or IV) *or steroid equivalent

• 2104 in the dexamethasone group vs 4321 in the “usual care” group
• Did not exclude children or pregnant/breastfeeding mothers
• Follow-up at 28 days, hospital discharge, or death

Primary outcome:         All-cause mortality at 28-days

Secondary outcomes: 

• Major arrhythmia
• Time to discharge from hospital
• Duration of mechanical ventilation
• Need for renal replacement therapy
• In patients not ventilated at enrollment, need for intubation/ECMO & death

Results:

• Decrease in overall mortality at 28-days with 3% absolute risk reduction.
  • NNT of 25 in patients requiring O2, HFNC, or NIV
  • NNT of 8 in patients requiring invasive mechanical ventilation
• More mortality benefit seen the higher the respiratory support required, with no benefit and apparent trend towards increased mortality in the group not requiring any respiratory support at all. 
• When stratified by symptoms < or > 7 days, mortality benefit only seen in the >7 days group (which was more of the ventilated patients).
• Less progression to intubation, shorter hospital duration, greater likelihood of hospital discharge.

Limitations:

• Not yet peer-reviewed, haven't seen all the data, additional analyses could be helpful in determining if treatment effect is real
• Unblinded study
• 7% of control group received dexamethasone

Bottom Line: Strongly consider admininstering dexamethasone to your patients with known COVID-19 who require respiratory support, and look for the peer-reviewed publication from the RECOVERY Trial investigators.

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Treatment for carpal tunnel syndrome (CTS)

The management of CTS depends of the severity of the disease

If symptoms or on the mild to moderate range, a trial of conservative treatment is encouraged.

Possible therapeutic approaches can include splinting in wrist neutral position. Some even extend to keep the CMP joints extended. Extreme flexion and extension can increase pressure within the carpal tunnel. Usually for nighttime use only. May be used during day based on work and activity demands.

Has been shown to improve electrophysiologic findings after 12 weeks of use in moderate CTS.

Formal hand physical therapy (by an experienced therapist) may also be of some benefit including carpal bone mobilization, ultrasound and nerve glide exercises.   

There is small evidence for the benefit of prednisone (20mg/d) as it has been shown to be more effective than placebo with improvements lasting an average of 8 weeks.

There is no benefit to NSAIDs or diuretics.

There is poor evidence for therapeutic ultrasound and acupuncture.

While more invasive than the above modalities, steroid injections may decrease inflammation and pressure in the carpal tunnel.  Patients randomized to steroid injection may do better than those randomized to nighttime splinting.

Early referral in those with positive electrodiagnostic findings is encouraged as they do best with earlier surgical release and have better recovery.

If however the patient has severe, progressive or persistent symptoms or there is known evidence of nerve injury on diagnostic testing, referral for surgical decompression is warranted.

Question

What is the name of the toxin found in this seed/bean and its mechanism of toxicity?

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• 2007091125_Bean_pic.jpg (32 Kb)

Idiopathic intracranial hypertension (IIH) is a vision-threatening illness with significant morbidity and needs to be considered as a possible headache diagnosis in the ED. Most often, this occurs in women of childbearing age with a BMI >30, but atypical varieties exist.

Symptoms: Headache (90%), visual disturbance, pulsatile tinnitus, horizotal diplopia.

Signs: Papilledema, 6th cranial nerve (abducens) palsy.

Evaluation: Neuroimaging including CTV or MRV to identify alternate cause including cerebral venous outflow obstruction, lumbar puncture with opening pressure >30 cmH₂O (25-30 cmH₂O is gray zone), blood work per clinical presentation, CSF analysis.

Treatment: No clear consensus, but typically acetazolamide. Severe or refractory symptoms may require surgical intervention such as optic nerve sheath fenestration, VP shunt, venous sinus stenting.

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We all know the frustration that comes with the phone call from radiology asking if you “really want IV contrast” for your patient’s CT because the creatinine is elevated…

Recently, a joint statement was published between the American College of Radiology and the National Kidney Foundation regarding the safety of IV contrast in patients with kidney disease. The recommendations are based on GFR and apply to those with both chronic kidney disease as well as those who have an acute kidney injury. Summary points of the statement are below:

• Prophylaxis is not indicated with a GFR > 45mL/min
• Prophylaxis should be given to patients with a GFR < 30mL/min (Other conditions such as heart failure or hypervolemia may preclude prophylaxis based on clinical judgement)
• Prophylaxis is NOT indicated in those with GFR > 30mL/min even if patients also have diabetes, dialysis dependent renal failure or those at risk of heart failure.
• High risk patients (Recent AKI, borderline GFR, or numerous risk factors) with GFR 30-44mL/min can be considered for prophylaxis based on clinical judgement

• Preferred prophylaxis is with isotonic fluid, such as normal saline. Volumes and timing are uncertain but should begin prior to contrast administration.
• Bicarbonate and N-acetylcysteine are not recommended fluids for prophylaxis

• There is no need for acute HD or CRRT following contrast administration in ESRD patients

Every decision to use contrast should be made based on clinical need for contrast as well as individual patient risk factors and underlying disease processes.

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Pain management can be challenging in patients with acute or chronic renal failure.  Opioid medications should always be used with caution, but some are safer than others.  Morphine and codeine specifically should be avoided in these patients due to accumulation of active metabolites that can prolong the duration of effect and adverse events. 

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Every year, numerous children die of non-exertional heatstroke after being left in motor vehicles in the United States. Per data obtained from the national nonprofit KidsAndCars.org, the average number of pediatric vehicular heatstroke deaths is 39 per year since 1990. In 2018, this number peaked at 54 pediatric deaths. Prior studies show that the interior temperature of a closed vehicle rises quickly within minutes of closing the doors and windows. This rapid change occurs even on days with cooler ambient temperatures (20s °C/70s °F): the interior temperature of a car may still reach 117F within an hour.

Children, particularly infants and toddlers, are at increased risk for heat illness due to several physiologic and developmental factors:

-       Unable to escape hot environments or to self-hydrate

-       Lack mature thermoregulatory systems

o   Have lower rate of sweat production than adults

-       Have higher basal metabolic rates than adults

-       Have higher body surface area:mass ratio --> absorb heat faster in hot environments

Bottom line:  ED providers can be instrumental in giving anticipatory guidance on vehicular heatstroke in children during the warmer seasons:

-        Educate caregivers to “Look before you Lock”

-       Suggest that the caregiver place a valuable object (phone, employee badge, handbag) in the back seat when traveling with a child

-       Remind caregiver of the dangers of intentionally leaving a child in the car for any reason, even during cooler spring/summer days.

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• 2007031141_Hammett._Pediatric_Heatstroke_Fatalities_Caused_by_Being_Left_in_Cars.pdf (581 Kb)

As has been previously noted, the white blood cell count is "the last refuge of the intellectually destitute."  However, within a CBC (especially if a differential is obtained), there is information that can sometimes be of value.  One measure, which was noted before COVID but has come under increasing attention in the current pandemic, is the Neutrophil-To-Lypmhocyte Ratio (NLR).  Because physiologic stress typically causes the Absolute Neutrophil Count (ANC) to increase and the Absolute Lymphocyte Count (ALC) to decrease, the ratio of the two values (NLR = ANC/ALC) should increase when the body is under stress.  Similar to the WBC however, it should be noted that ANY source of physiologic stress can cause abnormalities of the NLR, and thus this is not limited strictly to infectious etiologies.  

With that caveat in mind, the NLR can sometimes be a clue to the degree of physiologic stress the patient is under.  As lymphopenia is a frequent finding in COVID, the NLR has come under particular interest in the setting of COVID and appears to have prognostic value in COVID+ patients.

It should be kept in mind that inflammatory stressors (e.g. sepsis) are likely to disproportionately raise the NLR relative to noninflammatory stressors (e.g. pulmonary embolism), so a septic patient with an NLR of 10 might not be all that ill, whereas a PE patient with an NLR of 10 may be sicker.  As with any single lab, and particularly one so nonspecific, there are no hard and fast cutoffs, and the NLR has to be interpreted in the context of other clinical data (it is very much possible to have a high NLR and not be that sick, or to have a low NLR and be sick... this is only one datapoint and does have pitfalls associated with it).  As a rough guide however, a Pulmcrit post by Josh Farkas from 2019 suggested the following interpretation of the NLR:

1-3: Normal

6-9: Mild stress (e.g. uncomplicated appendicitis)

9-18: Moderate stress, may be associated with critical illness

>18: Severe stress, commonly associated with critical illness

The post (see references below) provides an excellent overview of NLR, further information on the uses and pitfalls of NLR, and several additional sources on the subject.  It's a very worthwhile read.  

Bottom Line: The Neutrophil-To-Lymphocyte Ratio (NLR = ANC/ALC) is one indicator of the degree of physiologic stress, and may be used in conjuction with other clues to determine how sick your patient is.  

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Carbon monoxide is an odorless gas that can cause neurologic and cardiovascular toxicity. It is produce by combustion of organic materials/fuel such as natural gas (furnace, gas stove, water heater, space heater) or gasoline.  DVT/PE has been reported among victims of CO poisoning. 

A recently published article investigated the risk of DVT/PE after CO poisoning. 

• Study design: cohort-cross over study (cross over at 1 year after CO poisoning)
• Setting: South Korea
• Data source: National Health Insurance Service database

Results

22,699 patients with CO poisoning were identified between 2004 and 2015

30 days after CO poisoning

• Risk of PE: OR of 22.0; 95% CI: 5.33 to 90.75
• Risk of DVT: OR of 10.33; 95% CI: 3.16 to 33.80

90 days after CO poisoning

• Risk of PE/DVT: OR of 3.96; 95% CI: 2.5 to 6.25

No significant increase in risk > 90 days.

Conclusion

• Patients are at highest risk of developing PE/DVT during first 30 days after CO poisoning.
• Increased risk of PE/DVT persisted up to 90 days after CO poisoning.

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